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Guidelines to the use
of antiretrovirals in the management of HIV infection

By Prof. B. Schoub

Antiretroviral therapy is complex and recommendations are continually being revised in line with current under-standing of the pathophysiology of HIV infection. Data from various clinical trials and especially recent evidence of the potent impact of combinations of drugs, and also the increasing avail-ability of monitoring tools, especially HIV-RNA viral load tests, continually modify treatment protocols.

Antiretroviral drugs
Over the past five years a number of new antiretroviral agents have been added to the benchmark standard of zidovudine. These agents fall into three categories:

The nucleoside analogue reverse transciptase inhibitors (NARTI)

  1. Zidovudine (AZT, Retrovir : Glaxo Wellcome)
  2. Didanosine (DDI, Videx : Bristol-Myers Squibb
  3. Zalcitabine (DDC, Hivid : Hoffman-La Roche)
  4. Lamivudine (3TC, Epivir : Glaxo Wellcome)

Non-nucleoside analogue reverse transcriptase inhibitors
  1. Nevirapine* (Viramune : Roxane/Boehringer Ingelheim)
    * Not yet licensed in South Africa

Protease inhibitors
  1. Saquinavir (Invirase : Hoffman-La Roche)
  2. Ritonavir * (Norvir : Abbott)
  3. Indinavir (Crixivan : Merck)

When to initiate therapy
The overall goal of antiretroviral therapy is to reduce the viral load as much as possible, and preferably so that it becomes undetectable (less than 200 -400 copies/mL).
Viral load studies have revealed the enormity of HIV turnover - up to 10 billion or more new HIV virions are produced every day and up to two billion CD4+ lymphocytes are destroyed daily. Because of this the International AIDS Society of the USA has adopted a more aggressive approach in its recommen-dations for therapy - earlier therapy with potent three drug combinations (Journal of the American Medical Association, June 25 1997, 277: 1962-1969).
In contrast the British HIV Association guidelines published in the Lancet, April 12 1997, 349:1086-92, have adopted a more conservative approach - initiating therapy with a two nucleoside analogue drug regimen and recommended only for patients with symptoms or laboratory markers indicating progression of disease.

Recommend therapy

  1. All patients with plasma HIV-RNA loads over 5 000 - 10 000 copies/mL irrespective of CD4+ cell count
  2. All symptomatic patients or patients with CD4+ cell counts of less than 500.

Consider therapy
All patients with any detectable HIV-RNA in plasma provided they are committed to lifelong compliance and adherence to the therapy. Discussions between patient and doctor are essential as long-term adherence to therapy is a major challenge and is critical to the success of therapy. If therapy is not meticulously adhered to this can lead to virus breakthrough and the development of drug resistant strains.

Deferral of therapy
Therapy may be deferred in the short term in patients with low plasma HIV-RNA counts and high CD4+ cell counts especially if conscientious long-term compliance cannot be guaranteed. These patients must, however, be monitored for viral load every 3-6 months. (These patients could include long-term non-progressors or slow progressors.)

Initial drug therapy
The recommended initial regimen is two nucleoside analogue reverse transciptase inhibitors and one protease inhibitor. The most widely used initial regimen is:

  1. Zidovudine 500 mg daily (100 mg 5 times/day) or 600 mg daily (200 mg 3 times/day)
  2. plus Lamivudine 150 mg b.d.
  3. plus Indinavir 800 mg t.d.s.

The majority of patients on this triple therapy regimen will reach the desired target of undetectable plasma RNA levels.

The alternate second-best recommendation is a combination of two nucleoside analogue reverse transcriptase inhibitors, e.g. Zidovudine plus didanosine plus a non-nucleoside analogue reverse transcriptase inhibitor (nevirapine).

Combination therapy with two nucleoside analogue reverse transcriptase inhibitors was recommended in previous International AIDS Society recommendations for initial therapy and remains a recommendation of the British HIV Association. It is, however, far less likely to achieve elimination of detectable HIV-RNA in the plasma and resistance is more likely to develop.

Monotherapy with any agent is not recommended for HIV therapy. The reduction in viral load on monotherapy is, at best, transient and resistance develops within weeks to months.

When to change therapy
Therapy would need to be changed if there is a) treatment failure; b) toxicity; and c) difficulty in adhering to the regimen.

a) Treatment failure: This would be indicated by
  1. Viral load monitoring indicating a failure of initial response to therapy. It is, however, important not to prematurely diagnose failure of the initial response. The drop in plasma HIV-RNA in response to treatment occurs in two phases - initial sharp drop within 2-4 weeks followed by a more gradual drop with maximal decline occurring only after 12-24 weeks.
  2. Return to pre-treatment viral load levels (within 0.12 to 0.2 log).
  3. Progressive drop in CD4+ count.
  4. Development of clinical disease or clinical deterioration.

What to change to

  1. All drugs in the regimen should be changed or at least two of the three. Alternate nucleoside analogue reverse transcriptase inihibitors or protease inhibitors should be substituted.
  2. Single drug changes are strongly discouraged because of the development of resistance.

b) Toxicity
Attempts must be made to identify the offending drug that should then be substituted with another member of the same class of drug.

c) Non-adherence
Reasons for non-adherence should be investigated and if necessary a simpler dosing regimen would need to be offered.

Treatment of primary infection (acute retroviral syndrome)
Primary infection should be treated aggressively and immediately as in theory it offers an opportunity to eradicate HIV infection. A triple drug therapy regimen, for example, zidovudine plus lamivudine plus indinavir should be instituted and therapy maintained until well after the plasma viral load has reached undetectable levels.

Costs
Costs, both of drugs as well as laboratory monitoring, remains a major consideration in the management of HIV infection, especially in South Africa. However, these costs need to be seen in the context of the prevention of opportunistic infections which are significantly delayed and treatment is considerably more costly than antiretroviral therapy. In addition, cognisance should be taken of the economic saving in returning productive young persons to work.

Definitions

  1. The CD4 count is the total count of CD4 lymphocytes in the blood. Healthy individuals would have a CD4+ count of 800 to 1 000. Values below 500/ul are indicative of immunosuppression and vulnerability to opportunistic infections. CD4+ lymphocyte counts of less than 300 and less than 200 are indicators of imminent opportunistic infection and are signals to commence chemoprophylaxis against tuberculosis (TB) and pneumocystis respectively.
  2. The HIV RNA is used as a measure for the number of copies of the HIV virus per unit of blood i.e. the viral load.

This article originally appeared in AIDS SA, Vol 6, No 2, 1997


Copyright 1999. The Diana, Princess of Wales, HIV Research Foundation. All rights reserved.
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